All eutherian mammals tolerate the engraftment of histoincompatible tissue during pregnancy. Yet, the maternal immune system remains competent to repel infection or to reject other forms of tissue allograft. Selective anergy to the placenta is one of the central unsolved mysteries of immunology. Since the placenta developed in an ancestral species that was endowed with a competent adaptive immune system, it is reasonable to suppose that this organism developed a mechanism for the circumvention of adaptive immunity to the trophoblast, and further, that the same core mechanism persists in its descendants today. It may be taken as axiomatic that a discrete set of maternally expressed genes is required for the maintenance of tolerance, and further, that mutations affecting these genes could disrupt tolerance. To approach the question of tolerance to the placenta, we have initiated a program of saturation mutagenesis in mice, employing a screen to detect mutations that forbid allogeneic (but not syngeneic) pregnancy. Three dominant mutations have been identified among 3506 F1 and F3 mice screened as of this writing. These mutations, and others that emerge, will be mapped and ultimately resolved through positional cloning methods. The identification of the gene(s) required for maintenance of selective tolerance to the fetal allograft will have several important consequences. First, it might ultimately be possible to take advantage of the toleragenic system utilized during mammalian gestation to promote the survival of other types of allograft: an outcome that would have important ramifications in transplantation medicine. Second, a similar or identical molecular system might be important in the maintenance of tolerance to self, and defects of the system might represent primary lesions in certain autoimmune diseases. Third, failure of tolerance to the placental allograft might be responsible for recurrent abortion as witnessed in humans and other mammalian species. Fourth, circumvention of the toleragenic mechanism might be used to prevent normal gestation, leading to termination of pregnancy within a few days following implantation of the blastocyst.